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Abstract

Adenosine plays important roles in cells, and impaired adenosine homeostasis has been associated with numerous human diseases. Lysosomes are referred as the cellular recycling centers which generate adenosine by breaking down lysosomal ATP. Recent studies have suggested that lysosomal adenosine accumulation causes phenotypes resemble Mucolipidosis type IV disease that is caused by mutations in TRPML1, a lysosomal ion channel. In this study, we have demonstrated that lysosomal adenosine is elevated by inhibiting or deleting adenosine deaminase (ADA) which degenerates adenosine. Lysosomal adenosine accumulation inhibits TRPML1 activity, which is rescued by overexpressing ENT3, the lysosomal membrane-bound adenosine transporter. Moreover, either ADA inhibition or ADA deficiency results in lysosomal dysfunction, and this is rescued by TRPML1 or ENT3 expression. Our data suggest that lysosomal adenosine accumulation inhibits TRPML1, and subsequently impairs lysosome function. This finding could lead to a new therapeutic strategy for human disorders caused by mutations in ADA and ENT3.